Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases

Probably not a substantial claim: may not pass S3 (load-bearing).

The catalytic subunit of Pol γ has DNA polymerase, 3′→5′ exonuclease and 5′-dRP lyase activities.

“The catalytic subunit has DNA polymerase, 3′→5′ exonuclease and 5′-dRP lyase activities (Graziewicz et al., 2006; Kaguni, 2004).”

• cites Graziewicz et al., 2006 sourceNot checked yet

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• cites Kaguni, 2004 sourceNot checked yet

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May combine two claims.

Over-expression of genes involved in the maintenance of thiol redox homeostasis or co-overexpression of Cu-Zn superoxide dismutase (Cu-ZnSOD) and catalase increase the lifespan of Drosophila melanogaster by 33-48%.

“Over-expression of genes involved in the maintenance of thiol redox homeostasis or co-overexpression of Cu-Zn superoxide dismutase (Cu-ZnSOD) and catalase increase the lifespan of Drosophila melanogaster by 33–48% (Orr et al., 2013; Orr and Sohal, 1994).”

• cites Orr et al., 2013 sourceNot checked yet

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• cites Orr and Sohal, 1994Not checked yet

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Classified as probably not a substantial claim.

Dysfunctional mitochondria have been implicated for decades in the process of aging and age-related diseases.

“As regulators of bioenergetics in the cell and the primary source of endogenous reactive oxygen species (ROS), dysfunctional mitochondria have been implicated for decades in the process of aging and age-related diseases.”

May combine two claims.

ROS and 8-oxo-dG are not major contributors to mtDNA mutations in WT organisms.

“Taken together, this suggests that ROS and 8-oxo-dG are not major contributors to mtDNA mutations in WT organisms.”

May combine two claims.

When either Cu-ZnSOD or catalase is over-expressed individually, only Cu-ZnSOD extends lifespan up to 48% while catalase has neutral or slightly negative effects.

“When either Cu-ZnSOD or catalase is over-expressed individually, only Cu-ZnSOD extends lifespan up to 48% while catalase has neutral or slightly negative effects (Sun and Tower, 1999).”

• cites Sun and Tower, 1999Not checked yet

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Mice deficient in either Cu-ZnSOD or MnSOD have widespread oxidative damage and hepatocarcinogenesis or neurodegeneration with reduced lifespan.

“For example, mice deficient in either Cu-ZnSOD or MnSOD have widespread oxidative damage and hepatocarcinogenesis or neurodegeneration with reduced lifespan (Elchuri et al., 2005; Lebovitz et al., 1996).”

• cites Elchuri et al., 2005 sourceNot checked yet

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• cites Lebovitz et al., 1996 sourceNot checked yet

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When human catalase is localized to peroxisomes or targeted to the nucleus in mice, no detectable reduction in mtDNA damage or significant extension of lifespan are observed.

“Interestingly, when human catalase is localized to peroxisomes or targeted to the nucleus in mice, no detectable reduction in mtDNA damage or significant extension of lifespan are observed (Schriner and Linford, 2006; Schriner et al., 2000).”

• cites Schriner and Linford, 2006Not checked yet

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• cites Schriner et al., 2000 sourceNot checked yet

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These same mice are protected from mitochondrial dysfunction, decreased energy metabolism and lipid-induced insulin resistance in skeletal muscle.

“These same mice are also protected from mitochondrial dysfunction, decreased energy metabolism and lipid-induced insulin resistance in skeletal muscle (Lee et al., 2010).”

• cites Lee et al., 2010 sourceNot checked yet

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Classified as probably not a substantial claim.

Mitochondrial DNA (mtDNA) is replicated and repaired by nuclear-encoded mtDNA polymerase γ (Pol γ) and several other associated proteins, which compose the mtDNA replication machinery.

“Mitochondrial DNA (mtDNA) is replicated and repaired by nuclear-encoded mtDNA polymerase γ (Pol γ) and several other associated proteins, which compose the mtDNA replication machinery.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Human mtDNA encodes 37 mitochondrial genes: 22 transfer RNAs, 2 mitochondrial ribosomal RNAs and 13 protein subunits of ETC complexes, with the exception of Complex II which is entirely nuclear encoded.

“It encodes 37 mitochondrial genes: 22 transfer RNAs, 2 mitochondrial ribosomal RNAs and 13 proteins subunits of ETC complexes, with the exception of Complex II which is entirely nuclear encoded.”

May combine two claims.

ogg1 or ogg1/mth1 knock-out mice have 20-fold higher levels of 8-oxoguanine in mtDNA and half the life expectancy relative to wild-type mice, but no increase in mtDNA mutations.

“The ogg1 or ogg1/mth1 knock-out mice have 20-fold higher levels of 8-oxoguanine in mtDNA (de Souza-Pinto et al., 2001) and half the life expectancy relative to wild-type (WT) mice (Xie et al., 2004), but no increase in mtDNA mutations (Halsne et al., 2012).”

• cites de Souza-Pinto et al., 2001Not checked yet

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• cites Xie et al., 2004 sourceNot checked yet

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• cites Halsne et al., 2012 sourceNot checked yet

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Errors caused by the mtDNA replication machinery and failure to repair these mtDNA errors result in mtDNA mutations.

“Here, we review evidence that errors caused by this replication machinery and failure to repair these mtDNA errors results in mtDNA mutations.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The Pol γ holoenzyme is a heterotrimer consisting of a single 140 kDa catalytic subunit and a 55 kDa accessory subunit that forms a dimer.

“The Pol γ holoenzyme is a heterotrimer consisting of a single 140 kDa catalytic subunit (nuclear encoded by POLG at chromosomal locus 15q25) and a 55 kDa accessory subunit that forms a dimer (nuclear encoded by POLG2 at chromosomal locus 17q24.1).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Human mtDNA is maternally inherited and exists as a circular, double-stranded genome organized into 16,569 base pairs.

“Human mtDNA is maternally inherited (Giles et al., 1980) and exists as a circular, double-stranded genome organized into 16,569 base pairs.”

• cites Giles et al., 1980 sourceNot checked yet

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Probably not a substantial claim: may not pass S4 (based).

Newer theories associate aging and mitochondrial dysfunction with clonally expanded mtDNA mutations caused by replication errors and altered mitochondrial dynamics.

“Newer theories associate aging and mitochondrial dysfunction with clonally expanded mtDNA mutations caused by replication errors and altered mitochondrial dynamics.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Support for the classical Mitochondrial Free Radical Theory of Aging (MFRTA) waned as new evidence linked ROS to both toxicity and signaling pathways associated with longevity.

“Support for the classical Mitochondrial Free Radical Theory of Aging (MFRTA) waned as new evidence linked ROS to both toxicity and signaling pathways associated with longevity.”

May combine two claims.

Kujoth et al. (2005) found no biomarkers of ROS induced damage to DNA, proteins or lipids, but report that tissue dysfunction is the result of apoptosis.

“Kujoth et al. (2005) found no biomarkers of ROS induced damage to DNA, proteins or lipids, but report that tissue dysfunction is the result of apoptosis.”

• cites Kujoth et al., 2005 sourceNot checked yet

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As ROS gradually increase over time, so do the cumulative levels of mtDNA damages, with ROS eventually reaching unstoppable toxic concentrations resulting in further mitochondrial dysfunction and aging.

“As ROS gradually increase over time, so do the cumulative levels of mtDNA damages, with ROS eventually reaching unstoppable toxic concentrations resulting in further mitochondrial dysfunction and aging.”

May combine two claims.

Trifunovic et al. (2004) also describe impaired OXPHOS with a reduction in ETC enzyme activities and decreased ATP production in mtDNA mutator mice.

“Trifunovic et al. (2004) also describe impaired OXPHOS with a reduction in ETC enzyme activities and decreased ATP production.”

• cites Trifunovic et al., 2004 sourceNot checked yet

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SOD knock-out mice (Sod2−/−) die within the first 10 days of life, while heterozygous mice (Sod2+/−) are viable with longevity and OXPHOS activity comparable to WT mice.

“Similarly, while SOD knock-out mice (Sod2−/−) die within the first 10 days of life (Li et al., 1995), heterozygous mice (Sod2+/−) are viable with longevity and OXPHOS activity comparable to WT mice (Mansouri et al., 2006).”

• cites Li et al., 1995Not checked yet

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• cites Mansouri et al., 2006 sourceNot checked yet

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In mitohormesis, high levels of ROS promote mtDNA damage and the aged phenotype, while low levels of ROS are signaling molecules that regulate stress response pathways and activate cellular processes that enhance lifespan.

“In this theory, high levels of ROS promote mtDNA damage and the aged phenotype, while low levels of ROS are signaling molecules that regulate stress response pathways and activate cellular processes that enhance lifespan (Hekimi et al., 2011).”

• cites Hekimi et al., 2011 sourceNot checked yet

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Mouse embryonic fibroblasts from mtDNA mutator mice produce normal amounts of ROS and demonstrate no increased sensitivity to oxidative stress.

“In a follow-up study to experimentally address the “vicious” cycle aspect of the MFRTA, mouse embryonic fibroblasts from mtDNA mutator mice are shown to produce normal amounts of ROS and demonstrate no increased sensitivity to oxidative stress (Trifunovic et al., 2005).”

• cites Trifunovic et al., 2005 sourceNot checked yet

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Inactivation of any of the five isoforms of SOD in Caenorhabditis elegans fails to decrease longevity, in spite of increased oxidative stress, and actually prolongs lifespan.

“On the other hand, inactivation of any of the five isoforms of SOD in Caenorhabditis elegans fails to decrease longevity, in spite of increased oxidative stress, and actually prolongs lifespan (Van Raamsdonk and Hekimi, 2012).”

• cites Van Raamsdonk and Hekimi, 2012Not checked yet

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Exonuclease-deficient Pol γ in pancreatic islet cells caused impaired glucose tolerance, diabetes, and increased apoptosis in β-cells.

“Exonuclease-deficient Pol γ pancreatic islet cells caused impaired glucose tolerance, diabetes, and increased apoptosis in β-cells (Bensch et al., 2007; Bensch et al., 2009).”

• cites Bensch et al., 2007 sourceNot checked yet

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• cites Bensch et al., 2009Not checked yet

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The mtDNA mutator mice appear normal through adolescence but develop a progeroid phenotype including alopecia, graying, kyphosis, osteoporosis, sarcopenia, weight loss, reduced subcutaneous fat, presbycusis, reduced fertility, anemia, cardiac hypertrophy, and a reduced lifespan.

“The mice appear normal through adolescence but develop a progeroid phenotype including alopecia (hair loss) and graying, kyphosis (curvature of the spine), osteoporosis (loss of bone density), sarcopenia (loss of muscle mass), weight loss, reduced subcutaneous fat, presbycusis (hearing loss), reduced fertility, anemia, cardiac hypertrophy (heart enlargement), and a reduced lifespan.”

• cites Kujoth et al., 2005 sourceNot checked yet

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• cites Trifunovic et al., 2004 sourceNot checked yet

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Mice heterozygous for the Pol γ mutation have no progeroid phenotype or reduced lifespan.

“Unlike the homozygous mtDNA mutator mice, mice heterozygous for the Pol γ mutation have no progeroid phenotype or reduced lifespan (Kujoth et al., 2005; Trifunovic et al., 2004).”

• cites Kujoth et al., 2005 sourceNot checked yet

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• cites Trifunovic et al., 2004 sourceNot checked yet

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There are no changes in the levels of antioxidants, protein carbonyls or aconitase enzyme activity in tissues of mtDNA mutator mice.

“There are also no changes in the levels of antioxidants, protein carbonyls or aconitase enzyme activity in their tissues.”

• cites Trifunovic et al., 2005 sourceNot checked yet

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WT and heterozygous mice mainly accumulate deletions at one hotspot between two 15-bp direct repeats, whereas homozygous mutant mice accumulate deletions regardless of the presence of direct repeats.

“WT and heterozygous mice mainly accumulate deletions at one hotspot between two 15-bp direct repeats, whereas homozygous mutant mice accumulate deletions regardless of the presence of direct repeats (Vermulst et al., 2008).”

• cites Vermulst et al., 2008 sourceNot checked yet

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Using the random capture method, heterozygous Pol γ mutant mice are found to have a 500-fold higher mutational burden than age-matched wild-type controls and a 30-fold increase over the oldest wild-type animals.

“However, using an adaptation of the more sensitive “random capture method,” which relies on PCR amplification of single molecules for mutation detection but is not limited by polymerase fidelity, the heterozygous mice are found to have a 500-fold higher mutational burden than age-matched wild-type controls and a 30-fold increase over the oldest wild-type animals (Vermulst et al., 2007).”

• cites Vermulst et al., 2007 sourceNot checked yet

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Of the handful of heterozygous mutations identified in POLG2, G451E and R369G are linked to PEO.

“Of the handful of heterozygous mutations identified in POLG2, G451E (Longley et al., 2006) and R369G (Craig et al., 2012; Young et al., 2011) are linked to PEO.”

• cites Longley et al., 2006 sourceNot checked yet

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• cites Craig et al., 2012 sourceNot checked yet

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• cites Young et al., 2011 sourceNot checked yet

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The resulting amino acid substitutions impair the stability of the ETC complexes, resulting in OXPHOS deficiency.

“The resulting amino acid substitutions impair the stability of the ETC complexes, resulting in OXPHOS deficiency.”

• cites Edgar et al., 2009Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

To date, there are over 300 disease-associated mutations in POLG listed in the Human DNA Polymerase Gamma Mutation Database.

“To date, there are over 300 disease-associated mutations in POLG listed in the Human DNA Polymerase Gamma Mutation Database (http://tools.niehs.nih.gov/polg).”

• cites http://tools.niehs.nih.gov/polgNot checked yet

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PEO manifests during adulthood and is characterized by bilateral ptosis and progressive weakening of the external eye muscles, proximal muscle weakness and wasting, skeletal muscle with ragged red fibers, impaired ETC enzyme activity, exercise intolerance, sensory ataxic neuropathy and respiratory failure due to muscle fatigue.

“PEO manifests during adulthood and is characterized by bilateral ptosis and progressive weakening of the external eye muscles, proximal muscle weakness and wasting, skeletal muscle with ragged red fibers, impaired ETC enzyme activity, exercise intolerance, sensory ataxic neuropathy and respiratory failure due to muscle fatigue.”

May combine two claims.

In a transgenic mouse model, human Pol γ encoding Y955C targeted to the heart causes cardiomyopathy, loss of mtDNA, increased 8-OHdG and premature death.

“In a transgenic mouse model, human Pol γ encoding Y955C was targeted to the heart. These mice develop a molecular signature of PEO in the heart with cardiomyopathy, loss of mtDNA, increased 8-OHdG and premature death (Lewis et al., 2007).”

• cites Lewis et al., 2007 sourceNot checked yet

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Most of the mutations in Pol γ are associated with arPEO; they are compound heterozygotes and often occur with common Pol γ mutations, such as A467T, W748S, R309L, G848S, R627W, N846S or T251I in cis with P587L.

“Most of the mutations in Pol γ are associated with arPEO. They are compound heterozygotes and often occur with common Pol γ mutations, such as A467T (Van Goethem et al., 2003a), W748S (Van Goethem et al., 2004), R309L (Lamantea et al., 2002), G848S (Lamantea et al., 2002), R627W (Van Goethem et al., 2003a), N846S (Van Goethem et al., 2003c) or T251I in cis with P587L (Lamantea et al., 2002; Scud”

• cites Van Goethem et al., 2003aNot checked yet

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• cites Van Goethem et al., 2004 sourceNot checked yet

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• cites Lamantea et al., 2002 sourceNot checked yet

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Both R943H and Y955C alter direct interactions with incoming dNTPs resulting in severely decreased processivity and a 99% decrease in polymerase activity.

“Both R943H and Y955C alter direct interactions with incoming dNTPs resulting in severely decreased processivity and a 99% decrease in polymerase activity.”

• cites Graziewicz et al., 2004 sourceNot checked yet

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May combine two claims.

The linear deleted mtDNA fragments are surmised to arise from stalled replication due to Pol γ exonuclease deficiency and do not contribute to the progeroid phenotype.

“Therefore, these fragments are surmised to arise from stalled replication due to Pol γ exonuclease deficiency and do not contribute to the progeroid phenotype (Kukat and Trifunovic, 2009).”

• cites Kukat and Trifunovic, 2009Not checked yet

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A heterozygous mutation in Pol γ that substituted a tyrosine with cysteine at codon 955 (Y955C) was first identified as a disease locus for adPEO while three more missense mutations were associated with arPEO.

“In 2001, a heterozygous mutation in Pol γ that substituted a tyrosine with cysteine at codon 955 (Y955C) was first identified as a disease locus for adPEO while three more missense mutations were associated with arPEO (Van Goethem et al., 2001).”

• cites Van Goethem et al., 2001 sourceNot checked yet

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Two sisters with early-onset PD, peripheral neuropathy and without PEO had a 37% decrease in mtDNA content with multiple deletions and were found to be compound heterozygous for two missense mutations (G737R and R853W) in Pol γ.

“Two sisters with early-onset PD, peripheral neuropathy and without PEO had a 37% decrease in mtDNA content with multiple deletions and were found to be compound heterozygous for two missense mutations (G737R and R853W) in Pol γ (Davidzon et al., 2006).”

• cites Davidzon et al., 2006 sourceNot checked yet

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May combine two claims.

The Y955C mutation has a wild-type catalytic rate, but a 45-fold decrease in binding affinity for the incoming dNTP.

“The Y955C mutation has a wild-type catalytic rate, but a 45-fold decrease in binding affinity for the incoming dNTP.”

• cites Ponamarev et al., 2002 sourceNot checked yet

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Patients with arPEO have the same clinical features as with adPEO, but with greater variation in symptoms and time of onset.

“Patients with arPEO have the same clinical features as with adPEO, but with greater variation in symptoms and time of onset.”

May combine two claims.

Edgar et al. (2009) reported frequent point mutations in ETC genes in homozygous mtDNA mutator mice, while heterozygous mice were not examined.

“Edgar et al. (2009) reported frequent point mutations in ETC genes in homozygous mtDNA mutator mice, while heterozygous mice were not examined.”

• cites Edgar et al., 2009Not checked yet

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Some diseases associated with POLG mutations manifest in adulthood and include symptoms of aging, namely autosomal dominant and recessive forms of Progressive External Ophthalmoplegia (adPEO/arPEO) and Parkinson's disease.

“Some associated diseases manifest in adulthood and include symptoms of aging, namely autosomal dominant and recessive forms of Progressive External Ophthalmoplegia (adPEO/arPEO) and Parkinson’s disease.”

May combine two claims.

Twinkle provides cardioprotection and could be a potential therapy for heart failure patients.

“This suggests Twinkle provides cardioprotection and could be a potential therapy for heart failure patients.”

May combine two claims.

A complete POLG2 knock-out is embryonic lethal in mice, but the heterozygous knockout (+/−) mouse has a normal phenotype.

“A complete POLG2 knock-out is embryonic lethal in mice, but the heterozygous knockout (+/−) mouse has a normal phenotype (Humble et al., 2013).”

• cites Humble et al., 2013 sourceNot checked yet

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Twinkle is essential for mtDNA maintenance and copy number.

“Twinkle is essential for mtDNA maintenance and copy number (Tyynismaa et al., 2004).”

• cites Tyynismaa et al., 2004 sourceNot checked yet

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Knockdown of porcine oocyte PolG2 causes an aging-like phenotype as evidenced by decreased production of ATP and maturation promoting factor (MPF), reducing the fraction of oocytes that reach MII stage.

“Knockdown of porcine oocyte PolG2 causes an aging-like phenotype as evidenced by decreased production of ATP and maturation promoting factor (MPF), reducing the fraction of oocytes that reach MII stage (Lee et al., 2015).”

• cites Lee et al., 2015 sourceNot checked yet

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Homodimeric mutants have problems stimulating PolG processivity, with G451E being more severely defective than R396G.

“Homodimeric mutants have problems stimulating PolG processivity, with G451E being more severely defective than R396G (Craig et al., 2012; Longley et al., 2006; Young et al., 2011).”

• cites Craig et al., 2012 sourceNot checked yet

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• cites Longley et al., 2006 sourceNot checked yet

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• cites Young et al., 2011 sourceNot checked yet

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The N-terminal domain of Twinkle is important for ssDNA binding and stimulation of the C-terminal helicase activity.

“The N-terminal domain is important for ssDNA binding and stimulation of the C-terminal helicase activity (Farge et al., 2007).”

• cites Farge et al., 2007 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Twinkle was classified as a helicase based on sequence similarity to bacteriophage T7 gene 4 primase-helicase (T7 gp4).

“It was classified as a helicase based on sequence similarity to bacteriophage T7 gene 4 primase-helicase (T7 gp4) (Spelbrink et al., 2001).”

• cites Spelbrink et al., 2001 sourceNot checked yet

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MGME1 has a role in mtDNA replication, likely providing 5′ → 3′ exonuclease activity.

“MGME1 interacts directly with PolG suggesting a role in mtDNA replication, likely providing 5′ → 3′ exonuclease activity (Nicholls et al., 2014).”

• cites Nicholls et al., 2014 sourceNot checked yet

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G451E homodimers fail to enhance binding of PolG to DNA, while R369G has weaker binding to PolG.

“G451E homodimers also fail to enhance binding of PolG to DNA, while R369G has weaker binding to PolG.”

• cites Craig et al., 2012 sourceNot checked yet

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• cites Longley et al., 2006 sourceNot checked yet

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• cites Young et al., 2011 sourceNot checked yet

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Helicase activity along with strand annealing activity of Twinkle has been confirmed, but no primase activity has been detected to date.

“Helicase activity along with strand annealing activity has been confirmed (Sen et al., 2012), but no primase activity has been detected to date.”

• cites Sen et al., 2012 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Twinkle has two domains, a primase-like N-terminal domain and a C-terminal helicase domain.

“Twinkle has two domains, a primase-like N-terminal domain and a C-terminal helicase domain (Shutt and Gray, 2006).”

• cites Shutt and Gray, 2006Not checked yet

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Twinkle is a 72 kDA hexamer/heptamer that functions as a 5′ → 3′ helicase for mtDNA replication.

“Twinkle is a 72 kDA hexamer/heptamer that functions as a 5′ → 3′ helicase for mtDNA replication (Korhonen et al., 2003).”

• cites Korhonen et al., 2003 sourceNot checked yet

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Twinkle is involved in D-loop formation and localizes to the nucleoid.

“It is involved in D-loop formation and localizes to the nucleoid (Jemt et al., 2015; Milenkovic et al., 2013; Spelbrink et al., 2001).”

• cites Jemt et al., 2015 sourceNot checked yet

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• cites Milenkovic et al., 2013 sourceNot checked yet

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• cites Spelbrink et al., 2001 sourceNot checked yet

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In adult human hearts, mtDNA has been shown to exist as dimers and is organized into highly complex, branched molecules.

“In adult human hearts however, mtDNA has been shown to exist as dimers and is organized into highly complex, branched molecules (Pohjoismaki et al., 2009).”

• cites Pohjoismaki et al., 2009 sourceNot checked yet

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Knockdown of RNase H1 in human bone osteosarcoma cells (143B TK-) led to lower mtDNA copy number and complete stalling of replication.

“Knockdown of RNase H1 in human bone osteosarcoma cells (143B TK-) led to lower mtDNA copy number and complete stalling of replication (Ruhanen et al., 2011), suggesting RNase H1 is vital for mtDNA replication.”

• cites Ruhanen et al., 2011 sourceNot checked yet

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31 dominant and 3 recessive Twinkle mutations have been recognized, the majority of which cause age-related disease.

“In all, 31 dominant and 3 recessive mutations have been recognized, the majority of which cause age-related disease (Sanchez-Martinez et al., 2012; Spelbrink et al., 2001).”

• cites Sanchez-Martinez et al., 2012 sourceNot checked yet

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• cites Spelbrink et al., 2001 sourceNot checked yet

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Depletion of any one of Mfn1, Mfn2 or OPA1 results in severe dysfunction in respiratory capacity and fragmentation of mitochondria.

“Depletion of any of one these proteins results in severe dysfunction in respiratory capacity and fragmentation of mitochondria (Chen et al., 2005; Chen et al., 2010; Song et al., 2009)”

• cites Chen et al., 2005Not checked yet

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• cites Chen et al., 2010 sourceNot checked yet

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• cites Song et al., 2009 sourceNot checked yet

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Overexpression of adPEO Twinkle mutations in HEK293 cells causes an accumulation of replication intermediates, suggesting these mutations trigger replication stalling.

“Overexpression of adPEO Twinkle mutations in HEK293 cells cause an accumulation of replication intermediates suggesting that these mutations are triggering replication stalling (Goffart et al., 2009; Wanrooij et al., 2007).”

• cites Goffart et al., 2009 sourceNot checked yet

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• cites Wanrooij et al., 2007 sourceNot checked yet

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Caloric restriction decreases ROS production in rodents, particularly at Complex I, thereby preventing oxidative damage in mitochondria from heart, liver, skeletal muscle and brain.

“Originally, it was shown that CR decreases ROS production in rodents, particularly at Complex I, thereby preventing oxidative damage in mitochondria from heart (Gredilla et al., 2002), liver (Lopez-Torres et al., 2002), skeletal muscle (Lass et al., 1998) and brain (Sanz et al., 2005).”

• cites Gredilla et al., 2002 sourceNot checked yet

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• cites Lopez-Torres et al., 2002 sourceNot checked yet

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• cites Sanz et al., 2005 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Although oxidative capacity is improved by exercise, there are no changes in the mtDNA mutation load.

“However, others have reported that although oxidative capacity is improved, there are no changes in the mtDNA mutation load (Jeppesen et al., 2009; Taivassalo et al., 2006).”

• cites Jeppesen et al., 2009 sourceNot checked yet

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• cites Taivassalo et al., 2006 sourceNot checked yet

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Resistance training in a patient with the G12315A tRNAleu(CUN) point mutation significantly improved heteroplasmic ratios and increased the number of respiratory-competent fibers in muscle fibers.

“This activation is accomplished with either eccentric or concentric resistance exercise, as shown in a patient with the G12315A tRNAleu(CUN) point mutation, where resistance training significantly improved heteroplasmic ratios and increased the number of respiratory-competent fibers in muscle fibers (Taivassalo et al., 1999).”

• cites Taivassalo et al., 1999 sourceNot checked yet

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Caloric restriction induces mitochondrial biogenesis and increases respiration through activation of SIRT1 and its downstream induction of PGC-1α.

“For example, CR induces mitochondrial biogenesis and increases respiration through activation of sirtuin 1 (SIRT1), an NAD+-dependent histone deacetylase, and its downstream induction of PGC-1α (Chistiakov et al., 2014; Martin-Montalvo and de Cabo, 2013).”

• cites Chistiakov et al., 2014 sourceNot checked yet

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• cites Martin-Montalvo and de Cabo, 2013Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Fusion and fission are opposing actions that work together to maintain the number, size, shape and function of mitochondria.

“Fusion and fission are opposing actions that work together to maintain the number, size, shape and function of mitochondria (Chan, 2012).”

• cites Chan, 2012 sourceNot checked yet

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Insufficient mitophagy and autophagy contribute to the accumulation of mutant mtDNA and are a factor in aging and age-related diseases.

“As with the fission and fusion processes, insufficient mitophagy and autophagy contribute to the accumulation of mutant mtDNA and are a factor in aging and age-related diseases (Gaziev et al., 2014; Green et al., 2011; Hubbard et al., 2012; Rubinsztein et al., 2011).”

• cites Gaziev et al., 2014 sourceNot checked yet

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• cites Green et al., 2011 sourceNot checked yet

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• cites Rubinsztein et al., 2011 sourceNot checked yet

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May combine two claims.

Caloric restriction extends both medium and maximum lifespan and delays the onset of age-related diseases in yeast, C. elegans, rodents and Rhesus monkeys.

“CR has been shown to extend both medium and maximum lifespan and delay the onset of age-related diseases in a variety of species, including yeast (Kaeberlein et al., 2007), C. elegans (Lee et al., 2006), rodents (Masoro, 2009) and Rhesus monkeys (Colman et al., 2014).”

• cites Kaeberlein et al., 2007 sourceNot checked yet

  Not checked in the free run.

• cites Lee et al., 2006 sourceNot checked yet

  Not checked in the free run.

• cites Colman et al., 2014 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

For all targeted cell types, TFAM depletion leads to mtDNA depletion, mitochondrial transcript depletion and respiratory chain deficiency, except not reported for midbrain DA neurons.

“For all the targeted cell types, TFAM depletion leads to mtDNA depletion (not reported for midbrain DA neurons), mitochondrial transcript depletion (not reported for midbrain DA neurons) and respiratory chain deficiency, suggesting that TFAM is essential for mtDNA maintenance in vivo”

• cites Ekstrand et al., 2007 sourceNot checked yet

  Not checked in the free run.

• cites Li et al., 2000Not checked yet

  Not checked in the free run.

• cites Wredenberg et al., 2002 sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Aging is a multifactorial, progressive, biological process with mitochondria playing a central role.

“Aging is a multifactorial, progressive, biological process with mitochondria playing a central role.”

Probably not a substantial claim: may not pass S4 (based).

The MFRTA has lost favor because its fundamental notion of a "vicious" cycle of ROS generating ETC disruption, and hence more ROS, is based on anecdotal evidence.

“The MFRTA, once at the forefront of aging theory, has lost favor since its fundamental notion of a “vicious” cycle of ROS generating ETC disruption, and hence more ROS, is based on anecdotal evidence.”

May combine two claims.

Using Digital Deletion Detection (3D), Taylor et al. report that although the total deletion load increases in human brain with aging, the number and diversity of deletions remains constant.

“Using Digital Deletion Detection (3D), a newer technology that allows for the study of rare, low occurring mtDNA deletions, Taylor et al. (2014) report that although the total deletion load increases in human brain with aging, the number and diversity of deletions remains constant.”

• cites Taylor et al., 2014 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Crossing mice overexpressing TFAM with mito-mice leads to an overall increase in mtDNA content and copy number without a decrease in the amount of deleted mtDNA.

“Another mouse model system crossed mice overexpressing TFAM with the mito-mice that have mutant mtDNA carrying a deletion of 4696 bp leading to an overall increase in mtDNA content and copy number without a decrease in the amount of deleted mtDNA (Nishiyama et al., 2010).”

• cites Nishiyama et al., 2010 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The deletor mouse phenotypes can be attenuated with bezafibrate, but this treatment causes severe hepatic side effects.

“The deletor mouse phenotypes can be attenuated with a lipid-lowering agent, such as bezafibrate, however this treatment causes severe hepatic side effects (Yatsuga and Suomalainen, 2012).”

• cites Yatsuga and Suomalainen, 2012Not checked yet

  Not checked in the free run.

May combine two claims.

TFAM overexpression in rat pancreatic islet cells normalized Nd1 mRNA levels and restored glucose-induced ATP generation along with insulin secretion.

“TFAM overexpression in rat pancreatic islet cells normalized Nd1 mRNA levels and restored glucose-induced ATP generation along with insulin secretion (Gauthier et al., 2009).”

• cites Gauthier et al., 2009 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

TFAM deletion in mouse pyramidal neurons causes mitochondrial late-onset neurodegeneration (MILON), whereas deletion in mouse midbrain DA neurons leads to PD.

“TFAM deletion in mouse pyramidal neurons causes mitochondrial late-onset neurodegeneration (MILON) (Sorensen et al., 2001) whereas deletion in mouse midbrain DA neurons leads to PD (Ekstrand et al., 2007).”

• cites Sorensen et al., 2001 sourceNot checked yet

  Not checked in the free run.

• cites Ekstrand et al., 2007 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The Twinkle overexpression mouse attenuates VO-induced eccentric hypertrophy and improves cardiac function while suppressing production of mitochondrial ROS and subsequent redox-sensitive signals.

“This mouse attenuates VO-induced eccentric hypertrophy and improves cardiac function while suppressing the production of mitochondrial ROS and subsequent redox-sensitive signals (Ikeda et al., 2015).”

• cites Ikeda et al., 2015 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

High levels of ROS contribute to the aging phenotype through oxidative damage to cellular components, such as proteins and lipids.

“This does not imply that high levels of ROS do not contribute to the aging phenotype through oxidative damage to cellular components, such as proteins and lipids.”